Delta9-tetrahydrocannabinol (THC) is best known as a psychotropic agent. Yet, this agent also produces multiple non- psychotropic effects; in particular reducing immunologic competence. These effects raise the possibility that cannabinoids regulate inflammations occurring within the CNS. The work proposed here addresses the role of cannabinoids in the regulation of microglial cell activation. Microglial cells are immune cells that reside in the CNS and become activated in diseases such as multiple sclerosis and HIV encephalopathy. Activated microglial cells release toxins and cytokines that lead to remodeling of affected tissue. By analogy with peripheral macrophages, we hypothesize that the engagement of cannabinoid receptors on microglial cells tempers their activation process. This hypothesis is supported by the observation that cannabinoids inhibit CNS inflammation associated with experimental allergic encephalomyelitis, an animal model of multiple sclerosis. In addition, several small clinical studies indicate that patients with multiple sclerosis experience relief from symptoms with marijuana use. We propose to identify and characterize the cannabinoid signaling system in microglial cells. The specific aims are: 1: What types of cannabinoid receptors do resting or activated microglial cells express? 2: How are endocannabinoids generated by microglial cells? 3: Do microglial cells inactivated endocannabinoids? Understanding how cannabinoids interact with microglial cells is of particular interest because patients with multiple sclerosis and HIV encephalopathy often use these drugs for medicinal purposes, and because recent evidence implicates cannabinoid signaling pathways in the symptomatology of these diseases. Finally, because cannabinoids are immunoactive, characterization of the cannabinoid signaling system in microglial cells might lead to new pharmaceutical targets that could specifically temper inflammation of the CNS.